Study on Leiomyosarcoma, Liposarcomas and Synovial Sarcoma With Trabectedin (TRADITIONS)

Time to Secondary Resistance to Trabectedin After Interruption Versus Continuation in Responding Patients With Liposarcoma, Leiomyosarcoma and Synovial Sarcoma

Two arm, randomized, open-label study, to determine the best time to secondary resistance between responding patients who discontinue treatment and resumed Trabectedin at the time of progression versus patients who continued treatment until progression. T

Study Overview

• Status: Withdrawn
• Conditions: Leiomyosarcoma; Liposarcoma; Synovial Sarcoma
• Intervention / Treatment: Drug: Trabectedin continuation; Drug: Trabectedin discontinuation

Detailed Description

This is an Italian, multicenter, randomized, open-label , two arm, study, to determine the best time to secondary resistance between responding patients who discontinue treatment and resumed Trabectedin at the time of progression versus patients who continued treatment until progression. The aim is to evaluate the best clinical practice for responding patients as Trabectedin has an acceptable safety profile with no evidence of cumulative toxicity.

After signing informed consent and being assessed for eligibility criteria , eligible patients will start the trabectedin treatment.

All the patients who will complete 6 cycles of treatment without disease progression will be be randomized to continue Trabectedin versus "treatment interruption" followed by re-challenge at progression. Patients randomized to discontinue treatment will be candidate to other 6 cycles of treatment and if they do not progress, to another interruption. The treatment will be resumed again at progression for other 6 cycles and this scheme of treatment will be proposed until progression under Trabectedin.

The study will be conducted in Italy in approximately 12 centers, in order to recruit 330 evaluable patients over a 4 year period. The follow-up will last approximately 3 years.

• Study Type: Interventional
• Phase: Phase 3

Contacts and Locations

Study Locations

• Italy
  • Bologna, Italy, 40136
    • Istituto Ortopedico Rizzoli - Unit of Chemotherapy of Muscoloskeletal Tumors
  • Firenze, Italy
    • Azienda Ospedaliero UNIVERSITARIA CAREGGI DI FIRENZE
  • Milano, Italy, 20133
    • Fondazione IRCCS INT Milano
  • Napoli, Italy
    • Policlinico Federico II
  • Padova, Italy
    • IRCCS Istituto Oncologico Veneto (IOV)
  • Palermo, Italy
    • Ospedale Giaccone
  • Roma, Italy
    • Istituti Fisioterapici Ospitalieri di Roma
  • AL
    • Alessandria, AL, Italy, 15100
      • A.O. SS Antonio e Biagio e Cesare Arrigo
  • FC
    • Meldola, FC, Italy
      • Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori - IRST
  • MI
    • Milano, MI, Italy, 20141
      • Istituto Europeo di Oncologia
    • Rozzano, MI, Italy, 20089
      • Istituto Clinico Humanitas
  • PD
    • Aviano, PD, Italy, 33081
      • Centro di Riferimento Oncologico di Aviano
  • RM
    • Roma, RM, Italy, 00128
      • Policlinico Universitario Campus Biomedico
  • TO
    • Torino, TO, Italy, 10153
      • Ospedale Gradenigo
  • Torino
    • Candiolo, Torino, Italy, 10060
      • Fondazione Del Piemonte Per L'Oncologia Ircc Candiolo

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. The patient or legal representative must be able to read and understand the informed consent form and must have been willing to give written informed consent and any locally required authorization before any study-specific procedures, including screening evaluations, sampling, and analyses
2. Diagnosis of well differentiated/dedifferentiated liposarcoma, mixoid round cell liposarcoma, leiomyosarcoma or synovial sarcoma
3. Persistent or locally relapsed and/or metastatic disease
4. Pathology specimens available for centralized review (central review is not mandatory prior to start the treatment, but within a month from screening, tumor sample must be sent to central pathology reviewer for a retrospective diagnosis confirmation).
5. Age ≥ 18 years
6. Adequate bone marrow function
7. Adequate organ function,
8. Eastern Cooperative Oncology Group Performance Status ≤ 2
9. One or more previous systemic treatments with anthracyclines with or without ifosfamide (unless one or both are clinically contraindicated)
10. Measurable disease. Patient who received radiotherapy within 3 weeks form the treatment start, can be included as long there is a measurable lesion outside of the irradiation field
11. A minimum of 3 weeks since any previous chemotherapy treatment
12. Recovery from toxic effects of prior therapies to (Grade 1 or lower)
13. Female patients of child-bearing potential must have negative pregnancy test within 7 days before initiation each cycle of chemotherapy. Post-menopausal women must be amenorrhoeic for at least 12 months to be considered of non-childbearing potential. Male and female patients of reproductive potential must agree to employ an effective method of birth control throughout the study.

Exclusion Criteria:

1. Pregnant or breast-feeding women
2. Prior exposure to Trabectedin
3. Peripheral neuropathy, Grade 2 or higher
4. History of other malignancies (except basal cell carcinoma or cervical carcinoma in situ, adequately treated), unless in remission from 5 years or more and judged of negligible potential of relapse
5. Known central nervous system metastases
6. Active viral hepatitis or chronic liver disease
7. Unstable cardiac condition, including congestive heart failure or angina pectoris, myocardial infarction within six months before enrollment, uncontrolled arterial hypertension or arrhythmia
8. Active major infection
9. Previous treatment with any other investigational or not investigational agents within 14 days of first day of study drug dosing
10. Known history of human immunodeficiency virus infection
11. Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation of the study drugs
12. Other serious concomitant illnesses or any condition that may interfere with the subject's participation in the study or evaluation of the study results

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Trabectedin continuation; All the patients who will complete 6 cycles of trabectedin without disease progression, will continue trabectedin until progressive disease, unacceptable toxicity, patient or investigator decision	Drug: Trabectedin continuation; Patients who did not progressed after 6 cycles of trabectedin will continue the treatment until Progressive Disease or unacceptable toxicity; Other Names: Treatment continuation
Experimental: Trabectedin discontinuation; All the patients who will complete 6 cycles of trabectedin without disease progression , will discontinue trabectedin. The treatment will be resumed again at progression for other 6 cycles and this scheme of treatment will be proposed until progression under trabectedin.	Drug: Trabectedin discontinuation; Patients who did not progressed after 6 cycles of trabectedin will stop the treatment and resume drug in case of progression for other 6 cycles. The treatment will be resumed again at progression for other 6 cycles and this scheme of treatment will be proposed until progression under trabectedin.; Other Names: Treatment discontinuation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time secondary resistance to Trabectedin	Time secondary resistance to Trabectedin is the time from the first trabectedin dose to progression not amenable to treatment with Trabectedin, or death, whichever occurs first	Week 18

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Overall Survival is the time from the first trabectedin dose to death for any cause	month 6,month 12, month 18, month 24, months 30, month 36, month 42, month 48, month 54, month 60
Incidence of adverse event	Adverse events are evaluate from the first trabectedin dose throughout the study according to CTCAE 5.0	Week 9, week 18, week 27, week 36, week 45, week 54, week 63, week 72, week 81
Progression free survival	Time from the first trabectedin dose to time of onset of progression disease	Week 9, week 18, week 27, week 36, week 45, week 54, week 63, week 72, week 81

Collaborators and Investigators

• Sponsor: Italian Sarcoma Group
• Collaborators: PharmaMar
• Investigators: Principal Investigator: Roberta Sanfilippo, MD, Fondazione IRCCS INT di Milano

Publications and helpful links

General Publications

• Demetri GD, von Mehren M, Jones RL, Hensley ML, Schuetze SM, Staddon A, Milhem M, Elias A, Ganjoo K, Tawbi H, Van Tine BA, Spira A, Dean A, Khokhar NZ, Park YC, Knoblauch RE, Parekh TV, Maki RG, Patel SR. Efficacy and Safety of Trabectedin or Dacarbazine for Metastatic Liposarcoma or Leiomyosarcoma After Failure of Conventional Chemotherapy: Results of a Phase III Randomized Multicenter Clinical Trial. J Clin Oncol. 2016 Mar 10;34(8):786-93. doi: 10.1200/JCO.2015.62.4734. Epub 2015 Sep 14.
• D'Incalci M, Galmarini CM. A review of trabectedin (ET-743): a unique mechanism of action. Mol Cancer Ther. 2010 Aug;9(8):2157-63. doi: 10.1158/1535-7163.MCT-10-0263. Epub 2010 Jul 20.
• Sanfilippo R, Dileo P, Blay JY, Constantinidou A, Le Cesne A, Benson C, Vizzini L, Contu M, Baldi GG, Dei Tos AP, Casali PG. Trabectedin in advanced synovial sarcomas: a multicenter retrospective study from four European institutions and the Italian Rare Cancer Network. Anticancer Drugs. 2015 Jul;26(6):678-81. doi: 10.1097/CAD.0000000000000228.
• Grosso F, Dileo P, Sanfilippo R, Stacchiotti S, Bertulli R, Piovesan C, Jimeno J, D'Incalci M, Gescher A, Casali PG. Steroid premedication markedly reduces liver and bone marrow toxicity of trabectedin in advanced sarcoma. Eur J Cancer. 2006 Jul;42(10):1484-90. doi: 10.1016/j.ejca.2006.02.010. Epub 2006 Jun 5.
• Le Cesne A, Blay JY, Domont J, Tresch-Bruneel E, Chevreau C, Bertucci F, Delcambre C, Saada-Bouzid E, Piperno-Neumann S, Bay JO, Mir O, Ray-Coquard I, Ryckewaert T, Valentin T, Isambert N, Italiano A, Clisant S, Penel N. Interruption versus continuation of trabectedin in patients with soft-tissue sarcoma (T-DIS): a randomised phase 2 trial. Lancet Oncol. 2015 Mar;16(3):312-9. doi: 10.1016/S1470-2045(15)70031-8. Epub 2015 Feb 11.

Study record dates

Study Major Dates

• Study Start (Anticipated): February 28, 2019
• Primary Completion (Anticipated): October 1, 2025
• Study Completion (Anticipated): October 1, 2025

Study Registration Dates

• First Submitted: December 10, 2018
• First Submitted That Met QC Criteria: December 11, 2018
• First Posted (Actual): December 12, 2018

Study Record Updates

• Last Update Posted (Actual): May 13, 2019
• Last Update Submitted That Met QC Criteria: May 9, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: trabectedin; soft tissue sarcoma
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Connective Tissue; Neoplasms, Muscle Tissue; Neoplasms, Adipose Tissue; Sarcoma; Leiomyosarcoma; Liposarcoma; Sarcoma, Synovial; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Trabectedin
• Other Study ID Numbers: ISG TRADITIONS

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No